Chronic obstructive lung diseases including cystic fibrosis (CF), chronic lung disease (CLD) of prematurity (also known as bronchopulmonary dysplasia; BPD), chronic bronchitis (CB), emphysema, and chronic obstructive pulmonary disease (COPD) belong to the most common chronic diseases in Europe and Northern America. CF is the most common fatal hereditary disease in white populations, CLD is a frequent health problem associated with premature birth, and cigarette smoke induced COPD with chronic bronchitis and/or emphysema has evolved as the fourth leading cause of death worldwide. All chronic obstructive lung diseases are accompanied by various degrees of airway mucus obstruction, goblet cell metaplasia and chronic inflammation of the respiratory tract and the formation of emphysema, i.e. disturbance in the development and/or destruction of alveoli, ultimately resulting in respiratory insufficiency.
Chronic obstructive pulmonary disease is a leading cause of death worldwide, but its pathogenesis is not well understood. Previous studies have shown that airway surface dehydration in β-epithelial Na+ channel (βENaC)-overexpressing mice caused a chronic lung disease with high neonatal pulmonary mortality and chronic bronchitis in adult survivors. Cystic fibrosis (CF) lung disease is the most common genetic form of chronic obstructive pulmonary disease (COPD) and is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a protein that is a cAMP-dependent Cl− channel and regulates the epithelial Na+ channel (ENaC). In CF airway epithelia, CFTR-mediated Cl− secretion is defective, and ENaC-mediated Na+ absorption is increased. In vitro studies of primary human airway cultures suggested that these defects in vectorial ion transport resulted in airway surface liquid (ASL) volume depletion and adhesion of dehydrated mucus, which was predicted to impair normal ciliary function and efficient mucus clearance in CF airways. To further elucidate the role of ASL volume depletion in the in vivo pathogenesis of CF, a mouse model with airway-specific overexpression of ENaC was generated. In this mouse model, it was demonstrated (1) that overexpression of the β-subunit of ENaC (encoded by the Scnn1b gene) under control of the Clara cell secretory protein (CCSP) promoter was sufficient to increase airway Na+ absorption in vivo, (2) that elevated airway Na+ absorption caused ASL volume depletion and reduced mucus clearance, and (3) that deficient mucus clearance produced spontaneous lung disease sharing key features with CF and other forms of COPD, including substantial pulmonary mortality and airway mucus obstruction, goblet cell metaplasia, chronic neutrophilic inflammation, and impaired clearance of bacterial pathogens (Mall et al. 2004).
Together, the results from these in vitro and in vivo studies demonstrate that ASL volume depletion is a key mechanism in the pathogenesis of CF lung disease. Furthermore, cigarette smoke has recently been shown to decrease CFTR expression and cAMP-dependent Cl− secretion in vitro and in nasal respiratory epithelia of cigarette smokers in vivo. These data indicate that impaired ASL volume regulation may also be implicated in the pathogenesis of cigarette smoke-induced chronic bronchitis.
Mall et al. (2008) show that airway surface dehydration is sufficient to initiate persistent neutrophilic airway inflammation with chronic airways mucus obstruction and to cause emphysema in mice. These results suggest that deficient airway surface hydration plays a critical role in the pathogenesis of chronic obstructive pulmonary diseases of different etiologies and produced a mouse model to study the pathogenesis and test therapeutic interventions for chronic obstructive lung diseases in vivo.
So far, the in vivo pathogenesis of chronic obstructive lung diseases remains poorly understood, and the establishment of diagnostic and prognostic markers remains challenging.
Further, only limited therapies exist that target the symptoms of the disease rather than underlying mechanisms, such as bronchodilators (β-mimetics and anticholinergics), inhaled corticosteroids, mucolytics and antibiotics. Therefore, new diagnostic markers and new therapies targeting molecular mechanisms for effective prevention and treatment in chronic obstructive lung diseases are of high clinical and socioeconomic interest.
MicroRNAs (miRNAs) are a family of short regulatory RNAs that negatively control gene expression at the post-transcriptional level. Base pairing between the miRNA and the 3′-UTR of target mRNAs mediates specific translation inhibition and/or degradation of mRNA targets. miRNAs regulate numerous cellular processes as diverse as differentiation, proliferation and apoptosis. Moreover, cellular miRNAs are also important for the replication of pathogenic viruses (e.g., miR-122a facilitates replication of human hepatitis C), and small RNAs are also encoded by the genomes of several viruses to facilitate viral replication by suppressing cellular genes. Detection of differential expression of miRNAs in many cases has established the basis for miRNA functional analysis and the characterization of the important roles played by miRNAs. In addition, specific miRNA expression patterns can provide valuable diagnostic and prognostic indications in the context of human malignancies such as solid tumors and leukemias. miRNAs have also been identified as therapeutic targets and biomarkers, such as miR-208 as biomarker of myocardial injury (Ji et al., 2009).
There is a need for means and methods for the prevention of chronic pulmonary diseases, in particular of chronic obstructive pulmonary diseases, cystic fibrosis lung disease, and chronic lung disease of prematurity. There is a need for means and methods for the diagnosis, prognosis and therapy of said chronic pulmonary diseases.